Adefovir dipivoxil, with trade names Preveon® and Hepsera®, is a diester prodrug of adefovir. Adefovir is an orally-administered nucleotide analog reverse transcriptase inhibitor (ntRTI) used for treatment of hepatitis B.
The chemical name of adefovir dipivoxil is 9-[2-[[bis[(pivaloyloxy)methoxy]phosphinyl]-methoxy]ethyl]adenine. It has a molecular formula of C20H32N5O8P, a molecular weight of 501.48 g/mol and the following structural formula:

Processes for the manufacture of adefovir and adefovir dipivoxil have been described in U.S. Pat. Nos. 4,724,233, 4,808,716 and 6,451,340.
Adefovir dipivoxil is unstable to moisture and can degrade to several degradation products (Yuan et al., Pharmaceutical Research, Vol. 17, 1098-1103, 2000; U.S. Pat. No. 6,635,278). Therefore, desiccants such as silica gel or activated charcoal are typically required as packaging aids (U.S. Pat. No. 6,635,278). Adefovir dipivoxil has an aqueous solubility of 19 mg/mL at pH 2.0 and 0.4 mg/mL at pH 7.2. It has an octanol/aqueous phosphate buffer (pH 7) partition coefficient (log p) of 1.91.
The crystalline form of an active pharmaceutical ingredient profoundly affects its physical properties such as solubility, stability, dissolution rate and bioavailability.
Pharmaceutical cocrystals are attractive because they offer multiple opportunities to modify the chemical and/or physical properties of an active pharmaceutical ingredient (API) without making or breaking covalent bonds.
Novel pharmaceutical salt forms of adefovir dipivoxil having expected and improved properties are beneficial. The pharmaceutical properties of an API can be significantly altered by salt formation. For example, salt formation can lead to changes in organoleptic properties (taste acceptability) as well as solubility, stability (hydrolytic, photolytic, thermal, hygroscopic), permeability, compactability, and processability of the parent molecule. These changes can lead to improved bioavailability, manufacturability, stability and patient compliance. A saccharinate salt form, for example, may offer special advantages such as improved taste acceptability. Salt formation and the resulting alteration in performance of the salt compared to the parent compound is not predictable.
CA 2,514,733 contains a very lengthy list of compounds (including Adefovir) and possible co-crystal forming agents. However, details are only provided for selected examples such as Celecoxib:nicotinamide, Olazapine:nicotinamide, Itraconazole:succinic acid, Itraconazole:fumaric acid, Itraconazole:L-tartrate, Itraconazole:malic acid, Itraconazole hydrochloride:DL tartaric acid, Modafinil:malonic acid, Modafinil:glycolic acid, Modafinil:maleic acid, Fluorouracil:urea, Carbamazepine:nicotinamide, Carbamazepine:saccharin. Similar to other solid forms such as solvated or hydrated forms, cocrystal formation is not predictable.
For the foregoing reasons, there is a need for novel crystalline forms of adefovir dipivoxil with enhanced chemical and physical properties.